Oxo-steroids and process of making same



Patented Oct. 20, 1953 OXO-STEROIDS AND PROCESS OF MAKING SAME Karl Micscher, Riehen, and Albert Wettstein and Julius Schmidlin, Basel, Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit,

No Drawing. Application-July 25, 1950, Serial No. 175,882. In Switzerland July 27, 1949 11 Claims. (Cl. 260397.4)

The present invention relates to the preparation of steroids having a semi-cyclic double bond in the l7-position, and has particular reference to l'l-ketones and 2l-aldehydes. I

It is known to prepare l'l-ketones by degradation of the side chain of sterols and bile acids. Where the starting materials which are subjected to such degradation process are substituted in ring C-and particularly when the substituent is in 12-position--very bad yields are obtained in some cases. However, it has been found, according to the present invention, that ring C,-substituted compounds which contain a -17-positioned semi-cyclic double bond can be converted in good yield into 17-ketones. The invention therefore provides an efficient way for converting the aforesaid starting materials into the 17- ketones. Furthermore, the A -pregnene-21-als have hitherto been available only by tedious methods. They have been produced for example by the building up of a side chain on a 17-ketone, which was itself obtained by the total degradation of a sterol, bile acid or pregnane side chain. The present invention makes possible the direct production of the said aldehydes from corresponding pregnane or pregnene compounds. Some of these aldehydes, e. g. A"-3,12-diacyloxypregnene-2l-a1s and A -3-keto-l2-acyloxy-pregnene-21-als, are new. The latter compounds are of great importance in connection with the preparation of Cortisone.

Briefly stated, the aforesaid 17-ketones and 21- aldehydes are obtained according to the invention, by the splitting out of water, directly or indirectly, from secondary 20-o1s of the pregnane series which contain in l'l-position a hydrogen atom and in 2l-position a substituted methylidene group, with the formation of a double bond, then treating the resultant compounds with oxidizing agents, and isolating the so formed 1'7- ketones and A -pregnene-21-als.

The initial materials, secondary pregnane-20- ols and pregnene-ZO-ols, contain in 21-position a substituted methylidene group. Illustrative of starting materials for use in the present invention are the aryl substituted Zl-methylene compounds, such as benzylidene and naphthyl-methylidene derivatives which may be substituted or unsubstituted in the aromatic ring, and the 21- lurfurylidene compounds. These starting mat -r rials can also be further substituted in the steroid residue, as in the '7- and 11- and in particular in the 3- and 12-position, for example by keto groups, free or functionally converted hydroxyl groups, for example acetoxy, benzoyloxy, tosyloxy, al-koxy, such as methoxy or triphenyl methoxy groups, or halogen atoms. Moreover they can for example have double bonds in 4-, 5-, 9- or 11- position.

The requisite initial materials can be prepared for example by reduction of the keto group of corresponding derivatives of pregnane-20-ones and pregnene-20-ones in per se known manner. The splitting out of water in accordance with the present process can be carried out directly or indirectly. For the direct water splitting, there is suitable treatment with dehydrating agents, such as concentrated organic or inorganic acids or their anhydrides, for example fatty acids, hydrohalic acids and phosphorus pentoxide, or inorganic salts, for example zinc chloride or potassium bisulfate, and also catalytically active agents, such as iodine in the presence or absence of diluents. The employment, in this connection, of lowerorganic fatty acids, such as acetic acid, propionic acid, butyric acid and so on, is particularly advantageous. Thus for example on boiling of 3,12,20-trihydroxy-21-methylene-preglnanes with glacial acetic acid, the hydroxyl group in 3-position is acetylated, whereas that in 20- ,position is split off with formation of a 17,20- ,double bond and that in 12-position remains unaffected. In the indirect splitting out of water, the secondary 20-hydroxyl group is first replaced for example by halogen or by' another ester residue, for example the xanthogen ester residue, or .by an ether residue. Subsequently a hydroxyl group thus converted can be removed, for ex- .ample'by thermal decomposition or by treatment .with an agent which splits off acid or alcohol.

The resultant n -pregnenes are readily convertible into ketones and aldehydes by oxidation. It has been found that, starting forexample from secondary pregnane-20-ols and pregnene-20-ols which contain in 21-position a substituted methylidene group, 'l'I-ketones and .A -pregnene-21- als can be obtained by suitablychoosing the oxidation method. The course of the oxidation is especially influenced by substituents in ring C,

primarily by an esterified hydroxyl group in 12- position, l2-hydroxy compounds which are esterified in l2-position by a lower organic acid, e. g. acetic acid, under certain conditions of oxidation, yield mainly l'l-ketones, whereas these 12- hydroxy compounds which are esterified in 12- position by a higher organic acid, especially toluene sulfonic acid, give a good yield of A pregnene-21-als. This may be illustrated by the following formulae;

OAc OH:

UH-OH==GH;-O@H5- are C D .AcO

{Axidation \axidation CH3 CH:

, o oH-ciio For the oxidation, use may be made for example of compounds of hexavalent chromium, such as chromic acid or chromyl chloride, and also permanganates, ozonization and the splitting of the ozonides, the action of peroxides, such as benzo-peracid, phthalio mono-peracid or hydrogen peroxide, advantageously in the presence of osmium tetroxide, and the splitting of the glycols produced by the hydrolysis of the oxide ring or by the direct attachment of two hydroxyl groups to the double bond in each case, for example by means of chromic acid, lead tetra-acetate or periodic acid.

If double bonds are present in the steroid nucleus, these are suitably protected from oxidation in known manner for example'by means of halogen or hydrogen halide in cases where such protection is not rendered superfluous by the particular properties of the unsaturated system,

as for example in the case of a double bond with keto group in a-position or a double bond in 11,12-position. Moreover oxidizable substituents such as hydroxyl groups can. be protected in known manner for example by esteriflcation or etherification and after the oxidation, partially or wholly again liberated, as desired, for example by the action of hydrolyzing agents. If however a conversion is desired of free ring carbinol to keto groups, this can be carried out in known manner at the same time as the oxidation in fication of the process in which one of the intermediate products obtainable is employed as starting material and the remaining stages of the process are carried out. w

The products 'ofthe present invention are intended to find application as therapeutic agents or as intermediate products for the manufacture of therapeutic agents.

The following examples illustrate the invention the parts being by weight unless otherwise stated and the relationship of parts by weightand'parts by volume being the same aS th h logr to the liter.

Example 1 6.8 parts of crude 3a,12a,20-trihydroxy-21- benzylidene-pregnane are dissolved in 200 parts by volume of glacial acetic acid and the whole boiled for 6 hours under reflux. The acetic acid is thereupon distilled off in vacuum and the residue taken up in methylene chloride. The solution after washing with water, 2 per cent sodium bicarbonate solution and. Water is dried over sodium. sulfate and the filtrate concentrated by evaporation. The A -3a-acetoxy-l2a-hydroxyzl-benzylidene-pregnene oi the formula crystallizes from ether in colorless prisms which melt at 220-223 C. [a] =+73 (c=1.044 in chloroform) For the splitting off of the water, instead of glacial acetic acid, also formic acid or propionic acid can be used.

The 21-benzylidene-pregnane-20-o1 employed above is prepared for example as follows:

8.12 parts of 3a,l2a-diacetoxy-20-lceto-2l-benzylidene-pregnane and 24.5 parts of aluminum isopropylate are dissolved in. 360 parts by volume of anhydrous isopropanol and the mixture subjected to a slow distillation during 12 hours for removal of the acetone produced in the reduction. The reaction mixture which is finally concentrated to about parts by volume is allowed to cool, treated with 800 parts by volume of molar Rochelle salt solution and the separated triol taken upv in methylene chloride. It is washed with water, dried and evaporated. The crude 21-benzylidene-20-ol thus obtained is suitably subjected to splitting out of water and simultaneous partial acetylation prior to purification.

From ethyl acetate the pure 3a,12a,20-trihydroxy 21 benzylidene-pregnane crystallizes in colorless small needles which melt at 148-150 C. By heating for 2 hours with acetic anhydride in the presence of pyridine on the water bath, there is obtained from the triol a triacetate which melts Example 2 Through two dropping funnels there are simultaneously added in the course of 9 hours, with exclusion of oxygen and moisture, 500 parts by volume of a 0.0% molar solution of A -3a-acetoxy 12a. tosyloxy-2l-benzylidene-pregnene and '75 parts by volume of an 0.8 molar anhydrous ethereal solution of hydrogen peroxide to a stirred mixture of 50 parts of anhydrous sodium sulfate, 0.25 part of osmium tetroxide and 200 parts by volume of dry ether. In order to complete the oxidation, the reaction mixture is stirred for another 24 hours at room temperature, and then diluted with 1600 parts by volume of ether and for the removal of the osmium agitated for 24 hours with a solution of 6 parts of sodium sulfite in 500 parts by volume of water. The aqueous layer is then removed and extracted three times with 500 parts by volume of ether on acumen 5.. each occasion, and the combined ethereal solutions are washed in turn with water, 2% sodium bicarbonate solution, and water, then dried with sodium sulfate, and filtered and the ether distilled off. The residue is dissolved in 50 parts by volume of anhydrous pyridine and 30 parts by volume of acetic anhydride and the mixture allowed to stand at room temperature under moisture seal. After 16 hours the excess of pyridine and acetic anhydride and the acetic acid that has formed are distilled off under reduced pressure at not more than 25 C. The residue is taken up in ether and the solution washed consecutively with lN-hydrochloric acid, water, 2% sodium bicarbonate solution and water, then dried with sodium sulfate, filtered, and evaporated. The crude product smells strongly of benzaldehyde. By recrystallization from a mixture of ether and petroleum ether, it yields A -3aacetoxy 12a tosyloxy-pregnene-21-al of M. P. 150-151 C. It has the formula t osyloxy on;

JOH-CHO The compound gives with 1:4-dihydroxynaphthalene the Raudnitz and Puluj reaction characteristic of aldehydes.

In an analogous manner other A "-3a,l2a-diacyloxy-2l-benzylidene-pregnenes, such as the A17 3a. propionyloxy 12a benzoyloxy 21- benzylidene-pregnene, are oxidized to A -311,121 diacyloxy-pregnene 21 als, e. g. A -3a-propionyloxy-12a-benzoyloxy-pregnene-21-al.

The A 3a-acetoxy-12a-tosyloxy-2l-benzylidene-S-pregnene, for example, is prepared as follows:

1.5 parts of A -3a-acetoxy-12a-hydroxy-21- benzylidene-pregnene and 3.0 parts of p-toluenesulfochloride are allowed to stand at about 30 C. in 10- parts by volume of pyridine for 6 days with exclusion of moisture. The solution is then treated at C. carefully with 3 parts by volume of water, the tosylate precipitated by further addition of water, taken up in ether and Washed consecutively with Obit-hydrochloric acid, water, 0.5N-sodium bicarbonate and water. The dried ether solution is evaporated and the crude product crystallized from 95 per cent. ethanol. By recrystallization from hexane, the A 3a acetoxy 12'a-tosyloxy-21-benzylidenepregnene is obtained as colorless flat prisms of double melting point l-104 C. and 125-126" C. (with decomposition). [a] =+140 (c=1.044 in chloroform).

AcO-

Example 3 3.32 parts of A -3a-acetoxy-12a-tosyloxy-2l benzylidene-pregnene are dissolved in 1500 parts by volume of anhydrous ethyl acetate, the S0111-1- tion cooled to 40 C. and 1.2 incl-equivalents of ozone passed in. After blowing off the excess of ozone with nitrogen, the reaction mixture is heated to room temperature and then after the addition of 15 parts of palladium-calcium carbonate catalyst, shaken in a hydrogen atmosphere until no more hydrogen is taken up. .The

solution. filtered from catalyst, is evaporated to dryness in vacuum and the residue chromatographed over 120 parts of aluminum oxide. The

Example 4 2.7 parts of A -3a,l2a-diacetoxy-2l-benzylidene-pregnene are dissolved in 1500 parts by volume of anhydrous ethyl acetate, the whole cooled to -25 C. and 6.5 moi-equivalents. of ozone passed in. The excess of ozone is blown off with nitrogen shortly after the completion of the introduction and the solution, after addition of 200 parts by volume of glacial acetic acid and 57 parts of zinc dust, stirred for 1 hour at room temperature. The zinc dust is then filtered off and the liquid evaporated in vacuum. The residue is taken up in ether, the solution washed with 2 per cent. sodium carbonate solution and water, dried and evaporated. The crude neutral substance is chromatographed on 60 parts of aluminum oxide. With pure hexane, only low molecular splitting products are dissolved out. A hexane-benzene mixture (1:1) eluates the 3am..- diacetoxy-aetiocholane- 17-one of the formula.

( )Ac 5 on.

0 CH3 l ACO- parts by volume of pyridine and 20 parts by" volume of acetic anhydride. The reaction mixture is thereupon evaporated'in vacuum and the residue taken up in ether. The ethereal solution is washed consecutively with 0.5N-hydrochloric acid, water, 0.5N-sodium bicarbonate and water. dried and evaporated. The A "-3a,l2adiacetoxy- 21-benzylidene-pregnene crystallizes from Iether ,isopropyl ether in colorless small needles. On

introduction into'a block preheated to 1625C.

the substance melts, andmay afterwards solidify again completely and then'meltsflnally at 164-.

167 C. '[a] (0:1.Q49 in chloroform).

Example 5 A solution of 4.07 parts ofa' 3p,20p dihydroxy 7 ZI-benzyIidne-pregnene in B parts by volume of glacial acetic acid is boiled for 6 hours under reflux. The working up takes place according to the method described in Example 1. By recrystallization from ether there is obtained the A -BB-acetoXy-ZI- benzylidene pregnadiene of the formula CHI AcO

Instead of glacial acetic acid, there can also be used for the splitting out of water, formic acid or oxalic acid.

' The 21 benzylidene-pregnane-20-01 employed as starting material is prepared for example as follows:'

6.0? parts of A -3fl-hydroxy-20-keto-21-benzylidene-pre gnene and 2455 parts of aluminum isopropylate are dissolved in 480 parts by volume of anhydrous isopropanol and the mixture subjected to a slow distillation for 8 hours in order to remove the acetone produced in the reduction. The working up takes place as described in Example- 1. The "A -3fi,20-dihydroxy-21-benzylidene-pregnene is obtained from methylene chloride-petroleum' ether in colorless crystals which melt at 169 172 C. [a] 52 (0:1.028 in chloroform).

Example 6 A solution of 1.93 parts of A -3-keto-21- benzylidene-pregnadiene in 45 parts by volume of ethylene chloride and 250 parts by volume of 90 per cent. acetic acid as treated slowly at 25 C., with stirring, with a solution of 2.80 parts of chromium trioxide in 125 parts by volume of 90 per cent. acetic acid. After 16 hours the excess of chromium trioxide is carefully destroyed with sulfurous acid. The A -androstene-3,17-dione is isolated from the neutral oxidation product by chromatography on 50 parts of aluminum oxide. The substance eluated with hexane-benzene mixture (1:1), after recrystallization from ether-petroleum ether melts at 169-1'71 C. and exhibits a specific rotation Ea] =+198 (0:1.120 in chloreform). -In a mixed melting point test it proves to be identical with the substance of the formula known to be A -androstene- 3,17-dione.

In an analogous manner A -3-keto-2l-fur furylidene-pregnene is oxidized. to A -androstene- 3,17-dione. g

The 119 -3-keto-2l-benzylidene-pregnadiene 'employedas starting material is obtained from A -35-acetoxy-21-benzylidene-pregnadiene in the following manner:

A suspension of 2.15 parts of A -3;3 -aceto xy- 21-benzylitlene-preghadiene in 110 parts by vol- 8* ume of methanol is, after addition of 1.40 parts of potassium carbonate in 14 parts by volume of water, heated to boiling for 2 hours. After cooling the whole is filtered with suction, washed with methanol and water and dried. There is obtained in this manner the A -3fl-hydroxy-21- benzylidene-pregnadiene in colorless small needles which melt at 184-188 C. [a] =-99 (0:1.023 in chloroform).

For dehydrogenation 9.72 parts of the free hydroxy compound are treated with 1690 parts by volume of toluene and 200 parts by volume of cyclohexanone and the solution dehydrated by distilling of! toluene. Then 5 parts of aluminum isopropylate are added and the whole boiled for 30 minutes. The cooled mixture is subjected to the addition of 600 parts by volume of molar Rochelle salt solution and treated with steam. The separated ketone is, after cooling, taken up in methylene chloride, washed with water andthe dried solution evaporated. The A -3-keto 2l-benzylidene-pregnadiene crystallizes from ether in colorless prisms of double melting point 179-181 C. and 194-198" C. [a] =+37 (c: 1.175 in chloroform) What we claim is:

1. Process for the manufacture of oxo-steroids, which comprises splitting off water from secondary 20-o1s of the pregnane series which contain in 21-position an aryl substituted methylidene group, with the formation of a double bond, then treating the compounds obtained with an oxidizing agent and isolating the so formed 1'?- ke'tones and A -pregnene-21-als.

2. Process for the manufacture of oxo-steroids, which comprises splitting oiT water from secondary 213-015 of the pregnane series which contain in 21-position an aryl substituted methylidene group and in 3- and IZ-pcsition a member selected from the group consisting of 0x0, hydroxy, and esterified hydroxy groups, with the formation of a double band, then treating the compounds obtained with an oxidizing agent and isolating the so formed l7-ketones and A -pregnene-21-als.

3. Process for the manufacture of oxo-steroids, which comprises splitting off Water from a ring unsaturated 3-acyloxy-pregnene-20-cl which contains in 2l-position an aryl substituted methylidene group, with the formation of a double bond, then treating the compounds obtained with an oxidizing agent and isolating the so formed l'i-ketones and A "pregnene-21-als.

4. Process for the manufacture of oxo-steroids, which comprises splitting ofi water from a 3,12- d1acyloxy-pregnane-20-ol which contains in 21- position an aryl substituted methylidene group, with the formation of a double bond, then treatmg the compounds obtained with an oxidizing agent and isolating the so formed 1'7-ketones and A -pregnene-21-als.

5. In a process the step consisting of splitting off water from a secondary 20-01 of the pregnane series which contains in 21-position an aryl substituted methylidene group, with the aid of a lower organic fatty acid.

6. A process according to claim 1, wherein the n -pregnenes with an aryl substituted methylidene group in 21-position'obtained by splitting off water from the corresponding 20-ols of the pregnane series, are oxidized with the aid of an oxidizing agent selected from the group consisting of hydrogen peroxide in the presence of osmium tetroxide, chomio acid and ozon "7. In a process for the manufacture of 0x0- steroids, the'step of treating A -pregnene compounds which contain in 21-position an aryl sub- 9. The A"-3a-acetoxy-lza-tosyloxy-pregnencstituted methylidene group with an oxidizing 21-a1.

agent and isolating the so formed I'Z-ketones and 10. The A" 3c-prop1ony1oxy-12a-benzoy1oxy- A -pregnene-zl-als. pregnene-Zl-al.

8. The A -pregnene-21-a1s which contain in 5 11. The A -3-keto-12a-tosy1oxy-pregnene-21- 3-position a, member selected from the group a1.

consisting of oxo, hydroxy, tosyloxy, and hydro- KARL MIESCHER. carbon carboxylic acid acyloxy with from 2 to 7 ALBERT WET'ISTEIN. carbon atoms, and in 12-position a member se- JULIUS SCHMIDLIN. lected from the group consisting of tosyloxy and 10 hydrocarbon carboxylic acid acyloxy with from 2 N0 references dto 7 carbon atoms. 

1. PROCESS FOR THE MANUFACTURE OF OXO-STEROIDS, WHICH COMPRISES SPLITTING OFF WATER FROM SECONDARY 20-OLS OF THE PREGNANE SERIES WHICH CONTAIN IN 21-POSITION AN ARYL SUBSTITUTED METHYLIDENE GROUP, WITH THE FORMATION OF A DOUBLE BOND, THEN TREATING THE COMPOUNDS OBTAINED WITH AN OXIDIZING AGENT AND ISOLATING THE SO FORMED 17KETONES AND $17-PREGNENE-21-ALS. 